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RESEARCH INTERESTS

Congenital heart disease (CHD) represents the most common birth defect in humans and is affecting about 1% of all live-born infants. Despite major advances in biomedicine and surgery, CHDs remain a significant cause of morbidity and mortality in both children and adults. While congenital heart defects frequently result from perturbation of developmental gene networks, incomplete understanding of the underlying regulatory mechanisms often limits progress in the diagnosis, prevention and treatment of CHD.

We apply a combination of molecular genetics and functional genomics to study the gene regulatory mechanisms that orchestrate formation of the four-chambered heart during embryogenesis and that can trigger CHD when defective. In mammalian genomes, DNA-encoded “transcriptional enhancers” serve as key regulatory modules that can switch genes on and off in a cell type-specific manner and at great linear genomic distances from their target gene(s) (up to >1M basepairs). Importantly, sequence mutation or perturbation in cardiac enhancers has been linked to cardiac malformation and CHD. However, despite the availability of genome-wide technologies, prediction of genomic enhancer function remains challenging, and the cis-regulatory landscapes of most cardiac genes are still underexplored. Our research has the goal to functionally annotate regulatory DNA in human genomes by dissecting the enhancer landscapes underlying the complex expression patterns of key cardiac genes, such as developmental transcription factors (TF). Such mechanistic understanding of cardiac gene regulation will not only help us to better understand how cardiac cell lineages emerge and how cardiac morphogenesis is wired in mammalian genomes, but will also be valuable for advanced interpretation of genomic heart disease-associated variants from patients and enable to explore genetic strategies for regenerative heart repair.

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Our main areas of interest are:

1) Gene regulatory dynamics driving mammalian heart development and disease.

We are using CRISPR/Cas9 genome editing, transgenic fluorescent reporter tagging and single-cell profiling in mouse embryos to elucidate the cardiac enhancer landscapes of developmental genes essential for heart formation and function. Identification of cardiac enhancers and understanding of their cellular specificities and regulatory relationships in an in vivo model of four-chambered heart formation is important for the establishment of accurate mechanistic links between gene networks, development of cardiac structures and heart disease-associated mutations.

2) Decoding cardiac enhancer landscapes in a human organoid model for cardiogenesis.

In the framework of the HeartX project funded by the SNSF National Research Program 79 (NRP 79) to advance the 3Rs we are using human induced pluripotent stem cell (hiPSCs) -derived cardioids (Hofbauer et al., Cell, 2021) to study the enhancer landscapes underlying ventricular chamber formation in a human model of cardiogenesis. This project allows us to compare the genomic cis-regulatory modules underlying in vitro human and in vivo mouse cardiac chamber formation to pinpoint common and divergent regulatory circuitries.

3) Rewiring developmental gene networks for cardiac reprogramming.

Using CRISPR genome editing-based strategies for concerted programming of developmental TF activities we aim to enable cardiac trans-differentiation in target cell types. It is our goal to use this system to uncover genomic cis-regulatory modules in control of the cardiac reprogramming process which holds therapeutic potential for regeneration of infarcted cardiac tissue and heart muscle repair.

Our lab is located in the new research institute (Mu24) of the Department for BioMedical Research (DBMR) at the University of Bern and we are part of the Cardiovascular Diseases Program (CVD) of the DBMR and members of the Cardiovascular Research Cluster Bern (CVRC).

NEWS

Since November 2021 we are located in the brand-new DBMR research institute at Murtenstrasse 24, as part of the Cardiovascular Diseases Program (CVD).

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